Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

García‐Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Thuc, Ophélia Le; Szigeti‐Buck, Klara; Cai, Weikang; Meyer, Carola W.; Pfluger, Paul T.; Fernández, Adolfo; Luquet, Serge; Woods, Stephen C.; Torres‐Alemán, Ignacio; Kahn, C. Ronald; Götz, Magdalena; Horváth, Tamas L.; Tschöp, Matthias H.

doi:10.1016/j.cell.2016.07.028

Cited by 424 publications

(460 citation statements)

References 42 publications

(50 reference statements)

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“…Third, given that LDHA is selectively expressed in the astrocytes (21)(22)(23)(24) and that leptin enhances LDHA-dependent glucose sensing in the hypothalamus as currently described, leptin signaling and glucose-lactate metabolism could intersect within the astrocytes to improve whole-body metabolic control. This postulation is collaborative with findings indicating that leptin signaling in the astrocytes regulates feeding (27) and that insulin signaling in the astrocytes enhances central glucose sensing (28). In summary, we here report, for the first time to our knowledge, that leptin enhances LDHA-dependent hypothalamic glucose sensing to regulate glucose production in high-fat fed in vivo conditions.…”

Section: Discussionsupporting

confidence: 63%

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

Abraham

Rasti

Bauer

et al. 2018

Journal of Biological Chemistry

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Abstract:The responsiveness of glucose sensing per se to regulate whole-body glucose homeostasis is dependent on the ability of a rise in glucose to lower hepatic glucose production and increase peripheral glucose uptake in vivo. In both rodents and humans, glucose sensing is lost in diabetes and obesity but the site(s) of impairment remain elusive. We here first report that short-term high-fat feeding dirsupts hypothalamic glucose sensing to lower glucose production in rats. Second, leptin administration into the hypothalamus of high-fat fed rats restored hypothalamic glucose sensing to lower glucose production during a pancreatic (basal insulin)-euglycemic clamp and increased wholebody glucose tolerance during an intravenous glucose tolerance test. Finally, both chemical inhibition of hypothalamic lactate dehydrogenase (LDH) (achieved via hypothalamic LDH inhibitor oxamate infusion) and molecular knockdown of LDHA (achieved via hypothalamic lentiviral-LDHA shRNA injection) negated the ability of hypothalamic leptin infusion to enhance glucose sensing to lower glucose production in high-fat fed rats. In summary, our findings illustrate that leptin enhances LDH-A-dependent glucose sesning in the hypothalamus to lower glucose production in highfat fed rodents in vivo.The hallmark feature of Type 2 diabetes is traditionally viewed as insulin resistance resulting in elevated hepatic glucose production and impaired glucose uptake in peripheral tissues. However, a change in glucose responsiveness as defined as the ability of glucose sensing per se in regulating glucose production and uptake could also potentially contribute to glucose dysregulation in diabetes.For instance, studies conducted in both rodents and humans report that independent of changes in glucoregulatory hormones during the pancreatic clamps, a doubling of circulating glucose levels inhibits glucose production and stimulates peripheral glucose uptake in healthy conditions (1-3). However, the same increment in the plasma glucose levels fail to lower glucose production in diabetic rodents (1) and humans (2,3), thereby illustrating glucose unresponsiveness as a feature in diabetic conditions. Glucose unresponsiveness in obese individuals has been determined from a mathematical minimal model analysis following a frequently sampled intravenous (ivGTT) or oral glucose tolerance test. Indeed, a reduction in glucose responsiveness was associated with impaired glucose tolerance in obese individuals (4). As seen in humans, obese and diabetic rodents such as the leptin deficient ob/ob mice also display a loss of glucose sensing (5). Thus, the ability of glucose sensing per se to regulate its own metabolism is highly relevant in obesity and diabetes.To date, the site(s) of glucose sensing impairment that lead to glucose unresponsiveness in obesity and diabetes remain elusive. In this regard, a hypothalamic glucose sensing mechanism has been documented to maintain glucose homeostasis in the context of hypoglycemic-induced counter regulation (6) as well as short-t...

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Section: Discussionsupporting

confidence: 63%

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

Abraham

Rasti

Bauer

et al. 2018

Journal of Biological Chemistry

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“…Interestingly, García-Cáceres et al [34] have recently revisited this concept and showed that intact insulin signaling in astrocytes is required for brain glucose uptake and insulin transport across the blood-brain barrier (BBB). In fact, both astrocytic IR (GFAP-IR) and hypothalamus-specific astrocytic IR (Hyp-GFAP-IR) knockout mice showed a decrease in glucose availability in the CNS, which consequently impaired systemic glucose homeostasis [34]. Noteworthy, this study has provided compelling evidence to prove that glucose transport across the brain is at least in part dependent on astrocytic insulin signaling and nutrient availability.…”

Section: Insulin Action In the Hypothalamusmentioning

confidence: 99%

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Chen

Balland

Cowley³

2017

Neuroendocrinology

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The central link between obesity and type 2 diabetes is the development of insulin resistance. To date, it is still not clear whether hyperinsulinemia causes insulin resistance, which underlies the pathogenesis of obesity-associated type 2 diabetes, owing to the sophisticated regulatory mechanisms that exist in the periphery and in the brain. In recent years, accumulating evidence has demonstrated the existence of insulin resistance within the hypothalamus. In this review, we have integrated the recent discoveries surrounding both central and peripheral insulin resistance to provide a comprehensive overview of insulin resistance in obesity and the regulation of systemic glucose homeostasis. In particular, this review will discuss how hyperinsulinemia and hyperleptinemia in obesity impair insulin sensitivity in tissues such as the liver, skeletal muscle, adipose tissue, and the brain. In addition, this review highlights insulin transport into the brain, signaling pathways associated with hypothalamic insulin receptor expression in the regulation of hepatic glucose production, and finally the perturbation of systemic glucose homeostasis as a consequence of central insulin resistance. We also suggest future approaches to overcome both central and peripheral insulin resistance to treat obesity and type 2 diabetes.

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“…Disruption of insulin signalling in astrocytes afects glucose uptake crossing the blood brain barrier (BBB). It also reduces glucose-induced activation of POMC neurons and impairs hypothalamic mediated suppression of systemic blood glucose [106].…”

Section: Astrocytes In Hypothalamusmentioning

confidence: 99%

Neuroendocrine Control of Hepatic Gluconeogenesis

Mao¹,

Zhang²

2017

Gluconeogenesis

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Glucose is intricately regulated in human body through a complex network of hormonal and neuronal factors. A series of evidence suggests that the gastrointestinal tract and the central nervous system play prominent roles in the regulation of glucose and energy homeostasis. The gut senses the nutrient supply to co-ordinate the release of hormones that activate neuronal networks in the brain, leading to the subsequent modulation of hepatic glucose output via the gut-brain-liver axis. The gut hormones also act on multiple peripheral tissues to regulate glucose level through an insulindependent and/or -independent mechanism. The brain, especially the hypothalamus, could also response to the hormones such as insulin and leptin and diferent nutrients to modulate the glucose homeostasis. In this chapter, we review the gut-brainliver axis and the role of this organ interaction in the control of glucose homeostasis. A beter understanding of these pathways will provide novel strategies for improved glycaemic control.

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Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

Cited by 424 publications

References 42 publications

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

Leptin enhances hypothalamic lactate dehydrogenase A (LDHA)–dependent glucose sensing to lower glucose production in high-fat–fed rats

Hypothalamic Insulin Resistance in Obesity: Effects on Glucose Homeostasis

Neuroendocrine Control of Hepatic Gluconeogenesis

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